Fecal Calprotectin Level Reflects the Severity of <i>Clostridium difficile</i> Infection

Kim, Jieun; Kim, Heejung; Oh, Hyun Ju; Kim, Hyung Sun; Hwang, Youn Jee; Yong, Dongeun; Jeong, Seok Hoon; Lee, Kyungwon

doi:10.3343/alm.2017.37.1.53

Cited by 39 publications

(26 citation statements)

References 20 publications

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“…Recent work from our group and others has demonstrated that fecal calprotectin is associated with CDI in humans and high levels of calprotectin are correlated with increased disease severity (7,(13)(14)(15). We have further demonstrated that calprotectin is antimicrobial against C. difficile and calprotectin-mediated metal limitation is an essential host immune response during CDI (7).…”

supporting

confidence: 57%

“…Calprotectindependent nutritional immunity is essential to defend against CDI (7). However, recent studies have demonstrated that increased fecal calprotectin is a hallmark of severe CDI, suggesting that during severe infection, C. difficile must employ strategies to persist and thrive in the gastrointestinal tract despite nutritional immunity (7,(13)(14)(15). In this study, we explored a potential mechanism by which C. difficile competes with the host for transition metals during infection.…”

Section: Discussionmentioning

confidence: 99%

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ZupT Facilitates Clostridioides difficile Resistance to Host-Mediated Nutritional Immunity

Zackular

Knippel

Lopez

et al. 2020

mSphere

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Clostridioides difficile is a spore-forming bacterium that causes severe colitis and is a major public health threat. During infection, C. difficile toxin production results in damage to the epithelium and a hyperinflammatory response. The immune response to CDI leads to robust neutrophil infiltration at the sight of infection and the deployment of numerous antimicrobials. One of the most abundant host immune factors associated with CDI is calprotectin, a metal-chelating protein with potent antimicrobial activity. Calprotectin is essential to the innate immune response to C. difficile and increasing levels of calprotectin correlate with disease severity in both adults and children with CDI. The fact that C. difficile persists in the presence of high levels of calprotectin suggests that this organism may deploy strategies to compete with this potent antimicrobial factor for essential nutrient metals during infection. In this report, we demonstrate that a putative zinc (Zn) transporter, ZupT, is employed by C. difficile to survive calprotectin-mediated metal limitation. ZupT is highly expressed in the presence of calprotectin and is required to protect C. difficile against calprotectin-dependent growth inhibition. When competing against wild-type C. difficile, zupT mutants show a defect in colonization and persistence in a murine model of infection. Together these data demonstrate that C. difficile utilizes a metal import system to combat nutritional immunity during CDI and suggest that strategies targeting nutrient acquisition in C. difficile may have therapeutic potential. IMPORTANCE During infection, pathogenic organisms must acquire essential transition metals from the host environment. Through the process of nutritional immunity, the host employs numerous strategies to restrict these key nutrients from invading pathogens. In this study, we describe a mechanism by which the important human pathogen Clostridioides difficile resists transition-metal limitation by the host. We report that C. difficile utilizes a zinc transporter, ZupT, to compete with the host protein calprotectin for nutrient zinc. Inactivation of this transporter in C. difficile renders this important pathogen sensitive to host-mediated metal restriction and confers a fitness disadvantage during infection. Our study demonstrates that targeting nutrient metal transport proteins in C. difficile is a potential avenue for therapeutic development.

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supporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

ZupT Facilitates Clostridioides difficile Resistance to Host-Mediated Nutritional Immunity

Zackular

Knippel

Lopez

et al. 2020

mSphere

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“…Factors that trigger neutrophils elevate calprotectin. For example, infectious enteritis, diverticulitis, microscopic colitis and rheumatologic disease have been associated with increased FC levels [9][10][11][12][13]. In addition, increased FC levels were shown in patients with colorectal cancer, adenomas and juvenile polyps [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Proton pump inhibitor use is associated with elevated faecal calprotectin levels. A cross-sectional study on subjects referred for colonoscopy

Lundgren

Eklöf

Palmqvist

et al. 2019

Scandinavian Journal of Gastroenterology

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Objectives: Faecal Calprotectin (FC) is a sensitive marker for gut inflammation. However, slightly elevated FC levels are also common in subjects without inflammation. We investigated the association between FC and clinical factors including concomitant use of medical therapy in patients with a normal colonoscopy. Material and methods: Outpatients (n ¼ 1263) referred for colonoscopy, performed FC test (CALPRO) the day before the start of bowel preparation. All subjects answered questionnaires that included questions on the present and past health history, concomitant medical treatment and gastrointestinal symptoms (GSRS). A medical record chart review was performed to check for concomitant disease, cause of referral and the result of the colonoscopy including biopsies. Inclusion criteria were a normal colonoscopy. Exclusion criteria were inflammatory bowel disease, colon cancer and highgrade dysplasia. Results: Five hundred ninety subjects fulfilled the inclusion criteria and completed the study. Thirty-six per cent of the subjects had a FC >50 mg/g. In a logistic regression analysis, age (adjusted OR: 1.051; CI: 1.032-1.071), and the use of proton pump inhibitors (adjusted OR: 3.843; CI: 2.338-6.316), non-steroid anti-inflammatory drugs (adjusted OR: 2.411; CI: 1.162-5.002) and acetylsalicylic acid (adjusted OR: 2.934; CI: 1.085-3.448) were significantly associated with an elevated FC (>50 mg/g). Conclusions: More than one-third of the patients with a normal colonoscopy performed in clinical routine had a slightly elevated FC level. Our results emphasise the need for attention to age, the use of proton pump inhibitors, non-steroid anti-inflammatory drugs and acetylsalicylic acid in the interpretation of FC tests in clinical practice.

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“…Cechą charakterystyczną w przypadku zakażenia C. difficile (CDI) jest uszkodzenie komórek nabłonka okrężnicy i wytworzenie ostrej reakcji zapalnej. Jednym z biomarkerów stanu zapalnego jelit jest kalprotektyna (7,11). Kalprotektyna jest białkiem o wielkości około 36 kDa, występującym w postaci dimeru.…”

Section: Abstract: Calprotectin Clostridium Difficile Infection (Cdunclassified

“…Wyniki naszych badań wykazały zróżnicowany poziom stężenia kalprotektyny w przewodzie pokarmowym u osób z zakażeniem C. difficile, przy czym najniższe z tych stężeń było 4-krotnie wyższe niż górna granica przyjęta dla osób zdrowych (50 µg/g kału). W badaniach innych autorów stężenia kałowej kalprotektyny były istotnie wyższe u pacjentów z CDI, niż u osób, u których przyczyna biegunki była inna, oraz u osób zdrowych (1,5,7,13,15).…”

Section: Wyniki I Ich Omówienieunclassified

Assessment of fecal calprotectin concentration in samples from patients with Clostridium difficile infection

et al. 2018

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Introduction: Clostridium difficile infection (CDI) can cause of nosocomial diarrhoea and intestinal inflammation. Fecal calprotectin (fc) is a sensitive marker of intestinal inflammation, found to be associated with enteric bacterial infections as C. difficile infection (CDI). Materials and Methods: We evaluated faecal calprotectin (fc) levels using a Ridascreen® Calprotectin test (R-Biopharm AG) in faecal samples of CDI positive patients diagnosed by C. Diff Quik Chek Complete (TechLab; Blacksburg, VA, USA and Alere; Waltham, MA, USA) test. Statistical analysis was performed for correlation of fc levels with infection with different C. difficile PCR-ribotypes (RTs). The study involved two groups of faecal samples: 58 samples with glutamate dehydrogenase (GDH) plus TOX A/B positive and second group were 17 samples from healthy adults without diarrhoea and GDH/TOX A/B negative. All samples (n=75) were plated on CLO selective agar (bioMérieux, Marcy l’Etoile, France) to grow a C. difficile strain. RTs was defined using specific primers. Results: From 75 stool samples, 47 strains of C. difficile were cultured only from diarrheal patients. In 58 diarrhoeic stool samples, the range of calprotectin concentrations were 199.7-1137.15 μg/g (>150μg/g, elevated concentration), which indicates on inflammatory process. C. difficile strains belonged to the following RTs: RT 027 (n=39), RT 020 (n=4), RT 176 (n=2), RT 001 (n=1) and RT 017 (n=1). In the 17 samples from the healthy adults, the range of calprotectin concentrations was 12.1-25.3 μg/g stool (FC normal concentration C. difficile strain was not cultured. Conclusions: The study found a differentiated level of calprotectin in the gastrointestinal tract in patients with CDI. There were no statistically significant differences in the concentration of calprotectin between patients infected with RT027 and different PCR ribotypes than RT027 (p >0,05). However, it should be emphasized that these tests carried out on a small number of samples. Examination of relationship between level of calprotectin and genetic type of C. difficile causing CDI requires further investigation.

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Fecal Calprotectin Level Reflects the Severity of Clostridium difficile Infection

Cited by 39 publications

References 20 publications

ZupT Facilitates Clostridioides difficile Resistance to Host-Mediated Nutritional Immunity

ZupT Facilitates Clostridioides difficile Resistance to Host-Mediated Nutritional Immunity

Proton pump inhibitor use is associated with elevated faecal calprotectin levels. A cross-sectional study on subjects referred for colonoscopy

Assessment of fecal calprotectin concentration in samples from patients with Clostridium difficile infection

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